chr7-23106120-G-T

Position:

• chr7-23106120-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001031710.3(KLHL7):​c.94G>T​(p.Gly32Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KLHL7 NM_001031710.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.09

Genes affected

KLHL7 (HGNC:15646): (kelch like family member 7) This gene encodes a BTB-Kelch-related protein. The encoded protein may be involved in protein degradation. Mutations in this gene have been associated with retinitis pigmentosa 42. [provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KLHL7. . Gene score misZ 3.907 (greater than the threshold 3.09). Trascript score misZ 5.0301 (greater than threshold 3.09). GenCC has associacion of gene with PERCHING syndrome, retinitis pigmentosa 42, cold-induced sweating syndrome, retinitis pigmentosa.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL7	NM_001031710.3	c.94G>T	p.Gly32Cys	missense_variant	1/11	ENST00000339077.10	NP_001026880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL7	ENST00000339077.10	c.94G>T	p.Gly32Cys	missense_variant	1/11	1	NM_001031710.3	ENSP00000343273	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458204 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724928

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 05, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1011582). This variant has not been reported in the literature in individuals affected with KLHL7-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 32 of the KLHL7 protein (p.Gly32Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.018	D;D
Sift4G	Benign	0.093	T;D
Polyphen		1.0	D;D
Vest4		0.63
MutPred		0.41		Loss of MoRF binding (P = 0.1032);Loss of MoRF binding (P = 0.1032);
MVP		0.85
MPC		0.44
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.31
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1172652033; hg19: chr7-23145739;